Somatic Mosaicism in Fanconi Anemia: Molecular Basis and Clinical Significance

Chromosome fragility in patients with Fanconi anaemia: diagnostic implications and clinical impact

“…With a less conservative upper limit of 50% of aberrant cells, the incidence of mosaicism would increase to >20%. Similar criteria for the detection of mosaicism have been proposed for other specialised laboratories9 and our frequency of mosaicism is also within the range previously reported in other populations (15–25%) 18 20…”

Fanconi anaemia

“…51 Other observed mechanisms include spontaneous genotypic reversion 52 and functional correction of the mutation as a result of secondary sequence alterations in cis. 53 All may confer a selective advantage to the cell, which then repopulates the marrow and could lead to improved haemopoiesis.…”

In vivo reversion to normal of inherited mutations in humans

“…In one case of the delG mutation (heterozygous with 1806insA, see table 3) a hybrid cell clone was isolated that bore neither mutation but had an apparent ''crossing over'' of haplotype markers, consistent with an intragenic recombination that generated a wild-type allele. 51 Intragenic recombination appeared to have occurred in an additional patient carrying the 67(322)del G (heterozygous with a splice site mutation IVS 11-2aRg). This patient showed phenotypic cellular reversion but retained both mutations in revertant cells.…”

“…51 A gene conversion event is possible (but not proven because markers flanking both sides were not apparently available). 51 In the last FANC C patient described, the original mutation (CTTRCGT; LeuRArg) generates a CpG mutation hotspot, which reverts, not site specifically but via the CRT change commonly found at CpG hotspots, to become TGT (ArgRCys). The authors demonstrated that the LeuRCys change was compatible with normal function.…”